Increasing the biorelevance of simulated intestinal fluids for better predictions of drug equilibrium solubility in the fasted upper small intestine

Abstract

To date the importance of luminal species other than bile salts and phosphatidylcholine on drug equilibrium solubility in the fasted upper small intestine has been evaluated to a very limited extent. In this communication the importance of fatty acids, cholesterol, and proteins on solubility of four model lipophilic compounds was evaluated by including these components into previously proposed simulated intestinal fluids. Data were compared with ex vivo solubility data in aspirates reflecting the mean and the median luminal composition in the upper small intestine. It is concluded that estimation of solubility in aspirates reflecting the median luminal composition is better estimated when the presence of cholesterol and fatty acids is also simulated. In contrast, estimation of solubility in aspirates reflecting the mean luminal composition requires consideration of additional factors (e.g. buffer species identity, non-micellar colloidal structures, and lyso-phosphatidylcholine content).